Traumatic brain injury (TBI) is a major health problem in the veteran population. Traditionally, TBI-induced brain damage is thought to be limited to the acute and sub-acute periods after trauma. However, abundant evidence from both human and experimental studies strongly suggests that a single TBI can trigger a progressive, long-term neurodegenerative process. However, the underlying mechanisms are not well understood. Endoplasmic reticulum (ER) stress and abnormal protein accumulation are detected in the acute brain injury following TBI. These changes may contribute to neuronal death in the acute stage of brain injury. Unexpectedly, in our pilot study, we detected prolonged ER stress and unfolded protein response (UPR) activation at 3-21 days after the controlled cortical impact injury. Most importantly, post-TBI administration of docosahexaenoic acid (DHA, 22:6n- 3) attenuated ER stress, abnormal protein accumulation, and ubiquitinated-protein aggregate formation in the injured rat brains. These preliminary findings led us to hypothesize that: 1) TBI triggers sustained ER stress and the UPR activation during the post-injury recovery phase; 2) the prolonged ER stress, abnormal protein accumulation, ubiquitinated-protein aggregate formation, and ER stress-associated inflammation contribute to development of neurological deficits after TBI; 3) DHA may enhance long- term neurological function recovery after TBI, in part, via reducing ER stress and abnormal protein accumulation. These hypotheses will be tested in three Specific Aims: Aim 1: To determine a causal link between TBI-mediated chronic ER stress and abnormal protein accumulation and aggregate formation following TBI Aim 2: To investigate whether DHA-mediated inhibition of ER stress leads to reduction of abnormal protein accumulation as well as improved neurological function after TBI Aim 3: To investigate effects of DHA on reduction of ER stress-associated inflammation after TBI To date, there are no effective treatments yet proven to improve the long-term neurological function recovery after TBI. DHA is a nutritional supplement with well-established safety profile and multi-mechanistic neuroprotective properties. The goal of this study is to investigate a newly discovered function of DHA in blocking sustained ER stress, and ER stress-associated inflammation after TBI and its efficacy in improving the long-term neurological function. There have been no clinical trials investigating the effects of DHA dietary supplementation on the treatment or prevention of TBI. A positive outcome from this study, together with other preclinical studies, will further warrant a well- designed clinical trial to determine whether omega-3 polyunsaturated fatty acid supplementation may improve outcomes following mild TBI.